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PHILADELPHIA – The mutation of a gene that has been associated with neurodevelopmental disorders like autism spectrum disorder led to marked sleep disturbances in fruit flies, according to a new study from scientists in the Perelman School of Medicine at the University of Pennsylvania. The findings, published Wednesday in Science Advances, provide further evidence that sleep is linked to early neurodevelopmental processes and could guide future treatments for patients.

While sleep disruption is a commonly reported symptom across neurodevelopmental disorders, including autism, it is often treated clinically as a “secondary effect” of other cognitive or behavioral problems, according to senior author Matthew Kayser, MD, PhD, an assistant professor of Psychiatry and Neuroscience at Penn, who led the study with Natalie Gong and Leela Chakravarti Dilley, both MD/PhD students.

“Our paper shows that sleep problems are not arising because of these other issues, but rather, this gene acts in different brain circuits, at different periods of time during development, to independently give rise to each of these symptoms,” Kayser said. “Which is to say, we’re guessing that the genetic constellation or signaling pathway that leads to disorders like autism or depression can also lead to sleep problems in humans.”

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To identify a correlation between sleep and neurodevelopment, Kayser and his research team genetically manipulated Drosophila, or fruit flies, by individually “knocking down” each of 218 genes that have been strongly associated with risk for neurodevelopmental disorders in humans. They then observed how the flies — a remarkably powerful model for biomedical research — reacted. After observing the flies’ behavioral patterns, they saw that knocking down the gene Imitation SWItch/SNF (ISWI) made the fruit flies almost entirely unable to sleep. ISWI in fruit flies is homologous to SMARCA1 and SMARCA5 genes in humans that have been linked to various neurodevelopmental disorders. In addition to sleep deficits, the researchers found that knocking down ISWI also led to memory problems and social dysfunction. Surprisingly, the ISWI gene was found to act in different cells of the fly brain during distinct developmental times to independently affect each of these behaviors.

Importantly, even though sleep deficits appear to arise directly from dysfunction of a given gene, Kayser said that previous research suggests treatments like cognitive behavioral therapy for insomnia are still likely to be effective.  “Even if problems like sleep disruption or insomnia arise from really early problems in the brain’s wiring, we have every reason to believe that we can use existing treatments,” Kayser said.

The findings support the idea that treating sleep problems in children with neurodevelopmental disorders could potentially improve other symptoms. Future work will examine the potential for leveraging sleep as a modifiable risk factor in mitigating the severity of neurodevelopmental disorders.

“Now that we know that sleep deficits are a primary characteristic of early developmental origin in neurodevelopmental disorders, we can start to ask,” Kayser said, “whether improving sleep will also improve memory and social function.”

This research was supported by the National Institutes of Health (K08 NS09046, DP2 NS111996, and T32 HL07953). Penn researchers Charlette Williams, Emilia Moscato, and Milan Szuperak also contributed to this work.

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Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $8.6 billion enterprise.

The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $494 million awarded in the 2019 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center—which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report—Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is powered by a talented and dedicated workforce of more than 43,900 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2019, Penn Medicine provided more than $583 million to benefit our community.

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